Investigation of Staphylococcus aureus intracellular survival strategies using a new genetically encoded proliferation reporter system
Immunology
Final Report Abstract
Staphylococcus aureus is a leading cause of difficult-to-treat infections. The capacity of S. aureus to survive and persist within phagocytic cells is an important factor contributing to therapy failures and infection recurrence. Therefore, interfering with S. aureus intracellular persistence is key to treatment success. To achieve this, a better understanding of the molecular mechanisms underlying intracellular bacterial survival and persistence is required. In this project, we have investigated the molecular mechanisms leading to S. aureus persistence within macrophages using a strain of S. aureus that carrying the reporter system mKikumeGR that enables to distinguish physiologically active from inactive intracellular bacteria together with a dual RNA-seq approach. We found that the fate of S. aureus within macrophages was not driven by heterogeneity within the host cells but rather by variability within the bacterial population in their capacity to adjust to and survive in the specific intracellular compartment that they occupy. Thus, intracellular S. aureus exhibited disparate gene expression profiles depending on their physiological state with physiologically active S. aureus exhibiting greater expression of genes involved in protein synthesis and proliferation and physiologically inactive bacteria displaying higher expression of oxidative stress responserelated genes, silenced genes involved in energy-consuming processes and exhibited a dormant-like state. Furthermore, physiologically active, proliferating and inactive bacteria differed in the intracellular compartment where they resided as well as in the internalization pathway engaged. Our results indicate that with the progression of infection, intracellular S. aureus transits from a physiologically active state to a non-replicative dormant-like state by turning off major energy-consuming processes and remains viable. This process seems to be driven by the level of stress encountered in the intracellular niche. We propose that entering a non-replicative dormant-like state is a S. aureus survival strategy to overcome the adverse environment encountered within macrophages. The results of this study indicate that effective therapies to treat S. aureus infections should target not only replicating bacteria but also the intracellular physiologically inactive dormant S. aureus.
Publications
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Longitudinal proliferation mapping in vivo reveals NADPH oxidase-mediated dampening of Staphylococcus aureus growth rates within neutrophils. Sci Rep. 2019 Apr 5;9(1):5703
Seiß EA, Krone A, Formaglio P, Goldmann O, Engelmann S, Schraven B, Medina E, Müller AJ.
